The Florey lecture, 1989. Self-tolerance: the key to autoimmunity.

'Horor autotoxicus', as it was termed by Erhlich, is a rare clinical event despite the genetic potential of every individual to mount immune responses to self-antigens. This can be explained by the fact that the developing immune system learns to recognize self-antigens and to tolerate them. The key to autoimmunity therefore lies in unravelling the mechanisms of self-tolerance. Studies of conventional models of unresponsiveness have failed to provide a definitive answer owing to the difficulty in controlling for the large number of antigen-related variables associated with self-tolerance and in following the fate of individual clones of self-reactive lymphocytes which emerge in very low numbers from the pre-immune repertoire. These problems have now been overcome by creation of transgenic mice tolerant to endogenous antigens and containing high frequencies of autoreactive T or B lymphocytes. According to the results obtained to date, different mechanisms of tolerance induction operate for self-reactive T lymphocytes compared with B lymphocytes. Thus self-tolerance in T lymphocytes appears to depend largely on clonal deletion within the thymus. By contrast, self-reactive B lymphocytes are functionally silenced without undergoing deletion provided that the transgenic B lymphocytes express both IgM and IgD on their surfaces. This dichotomy makes good sense given that the T-lymphocyte repertoire once shaped within the thymus is not subject to further mutation whereas antigen receptors on mature B lymphocytes undergo hypermutation in the periphery.